RRP8, associated with immune infiltration, is a prospective therapeutic target in hepatocellular carcinoma.

BACKGROUND: Ribosomal RNA Processing 8 (RRP8) is a nucleolar Rossman fold-like methyltransferase that exhibits increased expression in many malignant tumours. However, the role of RRP8 in hepatocellular carcinoma (HCC) is still uncertain. We explored the relationships between RRP8 and prognosis and immune infiltration, as well as the putative pathological function and mechanism of RRP8 in HCC. METHODS: Analysis of RRP8 expression across cancers was performed by using multiple databases. Associations between RRP8 expression and clinicopathological factors were further examined. Gene enrichment analysis was used to identify various putative biological activities and regulatory networks of RRP8 in HCC. The relationship between RRP8 expression and immune infiltration was confirmed by single-sample gene set enrichment analysis (ssGSEA). Univariate and multivariate Cox regression analyses were conducted to assess the impact of clinical variables on patient outcomes. Furthermore, a nomogram was constructed to estimate survival probability based on multivariate Cox regression analysis. Functional validation of RRP8 in HCC was performed with two different systems: doxycycline-inducible shRNA knockdown and CRISPR-Cas9 knockout. RESULTS: RRP8 was markedly overexpressed in HCC clinical specimens compared to adjacent normal tissues. Further analysis demonstrated that RRP8 was directly connected to multiple clinical characteristics and strongly associated with various immune markers in HCC. Moreover, elevated RRP8 expression indicated an unfavourable prognosis. Our functional studies revealed that both knockdown and knockout of RRP8 dramatically attenuated liver cancer cells to proliferate and migrate. Knockout of RRP8 decreased the phosphorylation of MEK1/2 and ß-catenin-(Y654) signalling pathway components; downregulated downstream signalling effectors, including Cyclin D1 and N-cadherin; and upregulated E-cadherin. CONCLUSIONS: RRP8 is strongly implicated in immune infiltration and could be a potential therapeutic target in HCC.

In situ Mo-doped ZnIn2S4/Ni-Ni Hofmann-type coordination polymer composites for photocatalytic hydrogen evolution reaction.

Solar energy-assisted hydrogen production technology is an essential tool for exploring hydrogen energy. To date, semiconductors have been used as the primary photocatalyst to generate hydrogen via photocatalytic water splitting. However, the high photogenerated electron-hole recombination rate of semiconductor photocatalysts results in a low hydrogen production rate. Herein, the synergistic effect of Mo-ion doping and the incorporation of Ni-based Hofmann-type coordination polymer (Ni-Ni HCP) on the photocatalytic performance of ZnIn2S4 (ZIS) is investigated. The hydrogen production rate of the prepared in-situ Mo doped ZnIn2S4 wrapped Ni-Ni HCP (Ni-Ni HCP/Mo-ZIS) sample under visible-light irradiation is 26.7 mmol g-1h-1, which is 10 times that of pure ZIS. Hydrogen production rate test, microscopic characterization, and density functional theory calculation confirm that the proposed dual modulation approach (combined ion doping and heterogeneous structure construction) could effectively increase the photocatalytic efficiency of ZIS. The stability of prepared samples is also examined by four-cycle photocatalytic hydrogen production tests. The proposed integrated method opens a new route for advancing renewable energy technology towards a sustainable future.

A machine learning model identifies M3-like subtype in AML based on PML/RARα targets.

The typical genomic feature of acute myeloid leukemia (AML) M3 subtype is the fusion event of PML/RARα, and ATRA/ATO-based combination therapy is current standard treatment regimen for M3 subtype. Here, a machine-learning model based on expressions of PML/RARα targets was developed to identify M3 patients by analyzing 1228 AML patients. Our model exhibited high accuracy. To enable more non-M3 AML patients to potentially benefit from ATRA/ATO therapy, M3-like patients were further identified. We found that M3-like patients had strong GMP features, including the expression patterns of M3 subtype marker genes, the proportion of myeloid progenitor cells, and deconvolution of AML constituent cell populations. M3-like patients exhibited distinct genomic features, low immune activity and better clinical survival. The initiative identification of patients similar to M3 subtype may help to identify more patients that would benefit from ATO/ATRA treatment and deepen our understanding of the molecular mechanism of AML pathogenesis.

TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons.

Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

One-Step MOF-Templated Strategy to Fabrication of Ce-Doped ZnIn2 S4 Tetrakaidecahedron Hollow Nanocages as an Efficient Photocatalyst for Hydrogen Evolution.

Achieving structure optimizing and component regulation simultaneously in the ZnIn2 S4 -based photocatalytic system is an enormous challenge in improving its hydrogen evolution performance. 3D hollow-structured photocatalysts have been intensively studied due to their obvious advantages in solar energy conversion reactions. The synthesis of 3D hollow-structured ZnIn2 S4 , however, is limited by the lack of suitable template or synthesis methods, thereby restricting the wide application of ZnIn2 S4 in the field of photocatalysis. Herein, Ce-doped ZnIn2 S4 photocatalysts with hollow nanocages are obtained via one-step hydrothermal method with an ordered large-pore tetrakaidecahedron cerium-based metal-organic frameworks (Ce-MOFs) as template and Ce ion source. The doping of Ce and the formation of ZnIn2 S4 tetrakaidecahedron hollow nanocages with ultrathin nanosheet subunits are simultaneously induced by the Ce-MOFs, making this groundbreaking work. The Ce-doped ZnIn2 S4 with a nonspherical 3D hollow nanostructure inherit the tetrakaidecahedron shape of the Ce-MOF templates, and the shell is composed of ultrathin nanosheet subunits. Both theoretical and experimental results indicate that the doping of Ce and the formation of hollow nanocages increase light capture and the separation of photogenerated charge carriers.

DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation.

DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically 'recognizes' H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1's activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing.

Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH 'reader' module within BAHD1 in mammals.

BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis.

Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) 'recognizes' H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-L-lysine-binding 'cage' formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH-H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH 'reader'.

Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation.

In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.

Metal-Organic Framework-Derived p-Cu2O/n-Ce-Fe2O3 Heterojunction Nanorod Photoanode Coupling with a FeOOH Cocatalyst for High-Performance Photoelectrochemical Water Oxidation.

Rapid charge recombination and slow water oxidation kinetics are key drawbacks that limit the photoelectrochemical water splitting efficiency of Fe2O3. In this work, we designed and fabricated for the first time that a metal-organic framework (MOF)-derived p-Cu2O/n-Ce-Fe2O3 nanorod array photoanode for the photogenerated charge effectively separated and transported at the Cu2O/Ce-Fe2O3 p-n heterojunction interface through a built-in electric field. In addition, the MOF-derived porous Cu2O nanoparticles have a large surface area, and thus, can offer more surface active sites for water oxidation. As anticipated, the novel structure Cu2O/Ce-Fe2O3 photoanode showed superior photocurrent density (3.2 mA cm-2), excellent bulk charge separation efficiency (38.4%), and surface charge separation efficiency (77.2%). After further modification with the FeOOH cocatalyst, the photocurrent density of the FeOOH/Cu2O/Ce-Fe2O3 photoanode reached 4.2 mA cm-2 at 1.23 VRHE (V vs reversible hydrogen electrode), having a low onset potential of 0.63 VRHE.

Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7.

Polycomb-directed repression of gene expression is frequently misregulated in human diseases. A quantitative and target-specific cellular assay was utilized to discover the first potent positive allosteric modulator (PAM) peptidomimetic, UNC4976, of nucleic acid binding by CBX7, a chromodomain methyl-lysine reader of Polycomb repressive complex 1. The PAM activity of UNC4976 resulted in enhanced efficacy across three orthogonal cellular assays by simultaneously antagonizing H3K27me3-specific recruitment of CBX7 to target genes while increasing non-specific binding to DNA and RNA. PAM activity thereby reequilibrates PRC1 away from H3K27me3 target regions. Together, our discovery and characterization of UNC4976 not only revealed the most cellularly potent PRC1-specific chemical probe to date, but also uncovers a potential mechanism of Polycomb regulation with implications for non-histone lysine methylated interaction partners.

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.

Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.

Ordered mesoporous silica cubic particles decorated with silver nanoparticles: a highly active and recyclable heterogeneous catalyst for the reduction of 4-nitrophenol.

In this work, using a modified Stöber process, we synthesized ordered mesoporous silica cubic particles (OMS-C) and prepared a nanocatalyst (Ag-OMS-C) based on OMS-C with a high surface area via an in situ auto-reduction strategy. The as-prepared Ag-OMS-C nanocomposites demonstrated open mesopores (3.51 nm), a large specific surface area (540 m2 g-1) and a high pore volume (0.88 cm3 g-1). The catalytic reduction of 4-nitrophenol (4-NP) over the Ag-OMS-C nanocatalyst was almost complete within 150 s without stirring and the rate constant k (30 × 10-3 s-1) is much higher than those of other substrate-supported Ag nanocatalysts. Moreover, the Ag-OMS-C nanocomposites hold a stable catalytic efficiency over five reaction cycles. The results indicate that the Ag-OMS-C nanocatalyst exhibited high catalytic activity and good reusability toward the reduction of 4-NP, which might be attributed to the large specific surface area, the pore structure of the nanocatalyst, as well as the synergistic effect between OMS-C and AgNPs.

ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer.

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies.

Triple function nanocomposites of porous silica-CoFe2O4-MWCNTs as a carrier for pH-sensitive anti-cancer drug controlled delivery.

Cobalt ferrite nanoparticles loaded on multiwalled carbon nanotube (MWCNT) magnetic hybrids have been demonstrated to be promising magnetic resonance imaging contrast agents and drug carriers. However, the hydrophobic, less biocompatible characteristics and low loading capacity for the drug hamper their wide biological applications. To solve the above problem, an alternative strategy is to coat the MWCNTs@CoFe2O4 nanoparticles with a mesoporous silica (mSiO2) shell. Herein, the reasonable fabrication process results in successful coating mSiO2 on the as-obtained MWCNTs@CoFe2O4 nanoparticles, forming well-defined core-shell-structured MWCNTs@CoFe2O4@mSiO2 nanocomposites. The as-synthesized mesoporous nanocarrier possesses a high surface area and large pore volume for the loading of the drug, and has a superparamagnetic feature for drug targeting. Moreover, the anticancer drug doxorubicin (DOX)-loaded MWCNTs@CoFe2O4@mSiO2 nanoplatforms show an excellent pH-responsive drug release character within 48 h. Therefore, a novel nanocarrier based on MWCNTs@CoFe2O4@mSiO2 was proposed, and its potential application for targeted cancer therapy was highlighted.

A Novel Open-Framework Copper Borovanadate with Enhanced Catalytic Performance for Oxidation of Benzylic C-H Bond.

A novel open-framework copper borovanadate, with a 6-connected topological net and 1D 8-membered ring channels, has been obtained for the first time. The compound not only exhibits a unique -B3 O7 (OH)-Cu-B(OH)3 linkage and features the largest ratio between TM2+ (Cu2+ ) and the borovanadate anion, but also possesses enhanced catalytic performance, high recyclability, and stability during the oxidation of benzylic C-H bonds.

Cd3(MoO4)(TeO3)2: A Polar 3D Compound Containing d10-d0 SCALP-Effect Cations.

The new polar 3D cadmium molybdotellurite Cd3(MoO4)(TeO3)2 was obtained by means of a high-temperature solid-state method. Cd3(MoO4)(TeO3)2 is a monoclinic crystal system, and it exhibits the polar space group P21 (No. 4). The structure of Cd3(MoO4)(TeO3)2 can be viewed as a complicated 3D architecture that is composed of distorted CdOn (n = 6, 7) polyhedra, TeO3 trigonal pyramids, and MoO4 polyhedra. The compound features the first 3D NCS cadmium molybdotellurite with 1D 4- and 6-MR channels and a polar structure originating from the TeO3 groups, MoO4 groups, and displacements of d10 Cd2+ cations. The results were further confirmed by calculations of the net polarization. The UV-vis spectrum and thermal properties indicate that Cd3(MoO4)(TeO3)2 exhibits a broad transparent region and excellent thermal stability. SHG tests of Cd3(MoO4)(TeO3)2 revealed that its response is approximately the same as that of KH2PO4 at the same grain size between 105 and 150 µm and that it is phase-matchable.

LPS-induced expression of CD14 in the TRIF pathway is epigenetically regulated by sulforaphane in porcine pulmonary alveolar macrophages.

Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro. CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN. After 12 h of LPS stimulation, gene expression was significantly up-regulated, including TRIF, TRAF6, NF-κB, TRAF3, IRF7, TNF-α, IL-1ß, IL-6, and IFN-ß. LPS-induced TRAM, TRIF, RIPK1, TRAF3, TNF-α, IL-1ß and IFN-ß were suppressed by 5 µM SFN. Similarly, DNMT3a expression was increased by LPS but significantly down-regulated by 5 µM SFN. It showed positive correlation of CD14 gene body methylation with in LPS-stimulated AMs, and this methylation status was inhibited by SFN. This study suggests that SFN suppresses CD14 activation in bacterial inflammation through epigenetic regulation of CD14 gene body methylation associated with DNMT3a. The results provide insights into SFN-mediated epigenetic down-regulation of CD14 in LPS-induced TRIF pathway inflammation and may lead to new methods for controlling LPS-induced inflammation in pigs.

Synthesis, Characterization and Cytotoxicity of Novel Multifunctional Fe3O4@SiO2@GdVO4:Dy3+ Core-Shell Nanocomposite as a Drug Carrier.

In this study, multifunctional Fe3O4@SiO2@GdVO4:Dy3+ nanocomposites were successfully synthesized via a two-step method. Their structure, luminescence and magnetic properties were characterized by X-ray diffraction (XRD), scanning electronic microscope (SEM), transmission electron microscopy (TEM), photoluminescence (PL) spectra and vibrating sample magnetometer (VSM). The results indicated that the as-prepared multifunctional composites displayed a well-defined core-shell structure. The composites show spherical morphology with a size distribution of around 360 nm. Additionally, the composites exhibit high saturation magnetization (20.40 emu/g) and excellent luminescence properties. The inner Fe3O4 cores and the outer GdVO4:Dy3+ layers endow the composites with good responsive magnetic properties and strong fluorescent properties, which endow the nanoparticles with great potential applications in drug delivery, magnetic resonance imaging, and marking and separating of cells in vitro.

Employing a new 12-connected topological open-framework copper borovanadate as an effective heterogeneous catalyst for oxidation of benzyl-alkanes.

A new 12-connected topological open-framework copper borovanadate with a unique B/V ratio (20/12) and a -B3O7(OH)-Na(µ-OH)[B(OH)2]-B3O7(OH)- connection mode has been hydrothermally obtained and characterized. It not only features the first 3-D copper(II) borovanadate which possesses the largest ratio of TM(2+) and borovanadate anion, but also displays highly catalytic activities for the oxidation of benzyl-alkanes.